Baine Jonathan M, Duhoo Yoan, Doukov Tzanko, Desfosses Ambroise, Bisello Giovanni, Beio Matthew L, Bauer Olivia, Perduca Massimiliano, Bacia-Verloop Maria, Bertoldi Mariarita, Phillips Robert S, Gutsche Irina, Berkowitz David B
Department of Chemistry, University of Nebraska, Lincoln, Nebraska 68588, United States.
1 Univ. Grenoble Alpes, CEA, CNRS, IBS, F-38000 Grenoble, France.
ACS Catal. 2025 May 2;15(10):8204-8218. doi: 10.1021/acscatal.5c00326. eCollection 2025 May 16.
We present evidence that supports a 'correct hydrazone tautomer/Dunathan alignment model' for how α-hydrazino analogues of α-amino acids inhibit PLP enzymes. Described is the asymmetric synthesis of l- and d-α-hydrazino acid l-lysine analogues and their inhibition of lysine decarboxylase (LdcI) via kinetic analysis, stopped-flow spectrophotometry, and cryo-EM. We describe a similar investigation of the important anti-Parkinsonism drug, carbidopa, with its human DOPA decarboxylase (hDdc) target. Evidence is consistent with these three hydrazino analogues forming the catalytically relevant ketoenamine PLP-hydrazone tautomer in their target active sites, with the α-carboxylate groups, though insulated, aligning with the PLP-π-system in a Dunathan-model-like orientation. High-resolution cryo-EM structures of the LdcI holoenzyme (pdb 9E0M-2.1Å) and LdcI-bound l- and d-hydrazones (pdb 9E0O-2.0 Å; pdb 9E0Q-2.3Å) and the first X-ray crystal structure of hDdc-bound carbidopa (pdb 9GNS-1.93Å) support this 'correct tautomer' model. These insights are expected to guide future PLP enzyme inhibitor development.
我们提供的证据支持了一种关于α-氨基酸的α-肼基类似物如何抑制磷酸吡哆醛（PLP）酶的“正确腙互变异构体/杜纳森排列模型”。文中描述了L-和D-α-肼基酸L-赖氨酸类似物的不对称合成，以及通过动力学分析、停流分光光度法和冷冻电镜对它们抑制赖氨酸脱羧酶（LdcI）的研究。我们还描述了对重要的抗帕金森病药物卡比多巴及其人多巴脱羧酶（hDdc）靶点的类似研究。证据表明，这三种肼基类似物在其目标活性位点形成了催化相关的酮烯胺PLP-腙互变异构体，α-羧基基团虽然被隔离，但以类似杜纳森模型的方向与PLP-π体系对齐。LdcI全酶（pdb 9E0M-2.1Å）以及与LdcI结合的L-和D-腙（pdb 9E0O-2.0 Å；pdb 9E0Q-2.3Å）的高分辨率冷冻电镜结构，以及与hDdc结合的卡比多巴的首个X射线晶体结构（pdb 9GNS-1.93Å）支持了这种“正确互变异构体”模型。这些见解有望指导未来PLP酶抑制剂的开发。
